tbuckley/cabot-search huggingface dataset:
P08.08.A EXPLORATION OF SURVIVORSHIP ISSUES AND QUALITY OF LIFE IN A COHORT OF IDH MUTATED HIGH GRADE GLIOMA 5 YEARS FOLLOWING DEFINITIVE TREATMENT
Authors: S J Engel, J Yim, M Kastelan, H Wheeler, M Back
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Approximately 2000 people are diagnosed with brain cancer in Australia each year. Compared to glioblastoma patients, the IDH-mutated high-grade glioma (IDHmHGG) is a more favourable diagnosis; better prognosis and survival outcomes. Coupled with improved treatments, the IDHmHGG cohort is living longer which means treatment side effects (eg. fatigue, cognitive deficits, physical limitations etc.) can significantly impact their quality of life in the survivorship years. Hence there is a need to identify and determine the survivorship issues most pertinent for the IDHmHGG cohort. MATERIAL AND METHODS A mixed- METHODS cross-sectional study was conducted to investigate the relationship between socio-demographic, clinical factors and quality of life in the IDHmHGG cohort. Qualitative data collection consisted of a neuro-oncology clinician focus group (n=11) regarding survivorship issues and was contrasted with semi-structured patient interviews (n=27). Quantitative data collection (n=41) involved socio-demographic questions, the Functional Assessment of Cancer Therapy - Brain (FACT-Br) tool and The Hospital Anxiety and Depression Scale (HADS). RESULTS The results indicate that marital status, employment status, and treatment complications are strongly associated with quality of life in IDHmHGG patients. Being single and unemployed is associated with lower quality of life (p&amp;lt;0.05). Similarly, our findings show that psychological distress, specifically the presence of anxiety and depressive symptoms, is a major factor that can negatively impact the QoL in an IDHmHGG cohort. The order of ranking between clinician and patient identified issues only matched for physical limitations (ranked 3rd). Although not matched in ranking, both groups identified cognitive function, employment, social function, isolation and mental health as commonly experienced in the survivorship years. CONCLUSION This study highlights the importance of considering socio-demographic and clinical factors in the care and support of brain cancer patients. The most important finding of this study was that being single and unemployed negatively predicted QoL. Additionally, it is notable that our results show a discrepancy between clinician identified issues and patient identified issues. This finding suggests that in order to deliver patient-centred and meaningful care, there is a need to incorporate a more patient focused perspective. Future survivorship models of care for the IDHmHGG cohort should be co-designed with patients.
OS13.6.A SURVIVAL IS ASSOCIATED WITH CIRCULATING B-CELLS AND AGE AMONG OLIGODENDROGLIOMA PATIENTS
Authors: J W Taylor, G Warrier, H Hansen, L McCoy, T Rice, G Guerra, S Francis, J Clarke, P Bracci, K Kelsey, M Wrensch, A Molinaro, J Wiencke
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Though patients with oligodendroglioma have improved outcomes versus astrocytomas, there remains marked variability in their survival experience that is unexplained by known prognostic factors. Immunomethylomics uses DNA methylation as a substitute for flow cytometry to characterize immune cells in whole blood. We applied immunomethylomics to archived samples from patients with oligodendroglioma enrolled in the UCSF Adult Glioma Study (AGS) to assess the impact of immune-related characteristics on prognosis. MATERIAL AND METHODS We used immunomethylomics to evaluate immune cell fractions in archived whole blood from the AGS. We identified 141 patients with oligodendroglioma (IDH and TERT mutant, and 1p19q co-deleted) and compared them to other adult diffuse glioma subtypes (N = 347) and controls (N = 454). RESULTS The median age at diagnosis of the 141 oligodendrogliomas was 44 years (range 19 - 83), 57% were male, and 75% white. A total of 60% of patients had received chemotherapy, with or without radiation, prior to blood draw and 25% were taking dexamethasone at the time of sample collection. Oligodendroglioma patients had lower proportions of B cell fractions (total, memory, naïve) than people without glioma. Still, there were higher proportions of B cell (total, memory) and lymphocyte fractions (total, CD4-total and memory), basophil, eosinophil, and NK cells in oligodendrogliomas compared to other glioma subtypes. Median overall survival for the oligodendrogliomas was 17.5 years (95% CI 16.9 - NA) with median follow-up time of 12 years (95% CI 11 - 14). Recursive partitioning analysis delineated two statistically significantly different survival groups for oligodendroglioma patients based on an interaction between age at diagnosis and B naïve cell proportions. The group with the best outcome had a median survival of 24.2 years (95% CI 20.4 - NR) comprised of patients &amp;lt;/= 42 years of age with a higher proportion of B naïve cells (&amp;gt;1.91%) (N = 37). The group with the worse outcome had a median survival of 16.9 years (14.8 - NR) and included patients &amp;lt;/= 42 years of age with a lower proportion of B naïve cells (&amp;lt;/= 1.91%) (N = 28) OR patients &amp;gt; 42 years of age (N = 76) (p = 0.00032). Additionally, proportions of lymphocyte fractions (CD4 and CD8 total, memory, and naïve) were significantly lower in the worse outcome group. Grade or prior treatment did not differ between the groups. CONCLUSION We identified an interaction between age and B naïve cell proportions that distinguished survival outcomes for patients with oligodendrogliomas. Immunomethylomics is a powerful tool for assessing immune status and these findings suggest that blood-immune characteristics may play a vital role in the prognosis of patients with gliomas.
P19.07.A EXPRESSION STUDY OF SYNAPTIC PROTEINS BASSOON, DLG4, DLG1, MAGI2, SHANK1, AND HOMER1 IN GLIOMA
Authors: M Timmer, N Lauer, S Kuhl, R Goldbrunner
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND To thrive, glioma cells exploit pathways that are active in normal CNS cells, as well as in normal neurotransmitter signaling. In healthy excitatory synapses the postsynaptic submembrane space consists of multiprotein complexes called the postsynaptic density (PSD). The PSD is responsible for the structural organization, the functioning, and the regulation of neuronal signaling. The five MAGUK Proteins DLG4, DLG1, Magi2, Shank1, and Homer1 are part of the healthy PSD complex and play a crucial role not only in NMDA and AMPA receptor signaling. Investigating the role of these MAGUK proteins in glioma biology could bring further insight into which principal neurobiological features, including organization in communicating networks, are recapitulated by tumor cells of different stages in gliomas. MATERIAL AND Methods qPCR was used to determine expression levels of DLG4, DLG1, Magi2, Shank1, and Homer1 in 7 different glioma groups (GII, GIII, primary GBM before and after chemotherapy, secondary glioblastoma recurrence with and without chemotherapy). Western Blot was done for DLG4, DLG1, and Homer1. Immunohistochemical staining of frozen sections, paraffin sections and in vitro cells was performed. Results The expression levels of DLG4, DLG1, Magi2, Shank1, and Homer1 were reduced especially in high grade glioma compared to control tissue. A tendency of decreasing protein levels with increasing malignancy is visible for the majority of proteins. In cell culture all proteins were also present. siRNA experiments are ongoing. Conclusion The presence of these synaptic proteins in glioma tissue and moreover also primary cell culture could indicate a role in tumor biology and the connection of glioma cells with neuronal tissue.
P08.02.B NEEDS OF SUPPORT IN GLIOBLASTOMA - FROM THE PATIENTS’ PERSPECTIVE
Authors: P Ståhl, I Henoch, A Smits, B Rydenhag, A Ozanne
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with IDH-wt glioblastoma carry a poor prognosis with a rapidly progressive illness trajectory. It is clear that the disabling symptoms experienced throughout the course of the disease require different kind of support depending on the nature of the problems. Previous research has drawn attention to support needs for brain tumour in general, but there is a lack of data focusing on patients with glioblastoma. This study aimed to explore the need of support during the illness trajectory for patients with glioblastoma considered from their own perspective. MATERIAL AND METHODS Twelve individual interviews with patients with glioblastoma were conducted during 2022 in Sweden. The inclusion criteria were histologically confirmed diagnosis of IDH-wt glioblastoma since at least 2 months and age ≥ 18 years at the time of diagnosis. The focus of the interviews was on experiences and specific needs of support. The interviews took place on one occasion, at a location based on the participant's preferences. Three interviews were conducted face-to-face, eight via telephone and one was a video interview. Interviews were audio recorded and transcribed verbatim. The analysis process based on qualitative content analysis is still in progress, but preliminary data will be discussed. RESULTS The preliminary results indicate that persons with glioblastoma need support in how to handle troublesome symptoms as well as practical support with e.g., transport and work abilities. More specifically, they wanted help in finding coping strategies and how to overcome deteriorated executive abilities. They found it positive to have been attributed a specific contact to discuss such questions or problems. Knowing whom to turn to in troublesome situations contributed to a sense of security even if the contact was not used. Furthermore, they wanted healthcare to be easily accessible, and to use an empathetic approach for the individual. CONCLUSION The preliminary results indicate that patients with glioblastoma need person-centred support throughout the course of the disease. Support is needed at different organizational healthcare levels; partly on a more comprehensive level, where accessibility is emphasised as an important factor, but also on an individual level where the attitude by the health care staff is seen as an important part of the support from the healthcare system.
OS02.4.A IMPACT OF SURGERY ON SURVIVAL IN PATIENTS WITH MULTIPLE BRAIN METASTASES
Authors: A Sagerer, C Buszello, M Lucas, I Eyüpoglu, S Hennig, G Schackert, T Juratli
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Surgical resection of brain metastases (BM) alleviates symptoms and can improve patients’ survival. However, the benefit of resection in multiple BM is controversial due to patients’ limited life expectancy. Therefore, we investigated the impact of resection of multiple BM on patients’ survival. MATERIAL AND METHODS We reviewed clinical data from 544 patients (216 female, 328 male) who underwent surgery for BM in our hospital between 2010 and 2022. Overall survival (OS) was estimated using the Kaplan-Meier estimator. In addition, follow-up data, adjuvant treatment and tumor recurrence data were collected. RESULTS We identified 280 patients (51.5%) with one and 264 patients (48.5%) with two or more BM. Bronchial carcinoma represented the most common primary tumor entity (n= 185, 88 one and 97 multiple BM), followed by melanoma (n= 109, 44 one and 65 multiple BM), breast cancer (n= 54, 31 one and 23 multiple BM), gastro-intestinal tumor (n= 64, 39 one and 25 multiple BM) and lastly cancer of unknown primary (CUP) (n= 29, 11 one and 18 multiple BM). We then compared the survival between patients with a single with those with multiple BM. The median OS of all patients with one BM was with 11.6 months significantly longer than those with two or more BM (7.3 months, p&amp;lt; 0.001, 95% CI one vs. multiple BM: 8.6-14.5 vs. 6.2-8.4 months, respectively). Notably, 29.3% of patients with one BM and 16.5% with multiple BM lived longer than 24 months after resection (long-term survivor, p= 0.001). Regarding primary tumor histology, patients with breast cancer with a single BM had a significant longer OS with 19.7 compared to patients with multiple BM (5.0 months, p= 0.031). Remarkably, 33.3% of all long-term survivors with breast cancer had multiple BM. Patients with a single BM originating from other cancers showed a superior but yet not significant OS in comparison with their counterparts with multiple BM after resection. This included: gastro-intestinal cancer 12.2 vs. 6.5 months (p= 0.160), melanoma 11.6 vs. 7.3 months (p= 0.236) and CUP 3.0 vs. 2.7 months (p= 0.258). The long-term survivor rate of patients with resected multiple BM varied between 20.6% in melanoma and 7.4% in patients with CUP. CONCLUSION Despite limited prognosis in patients with multiple BM, surgical resection should be considered as an effective treatment option. Our study shows that a substantial subset of patients with multiple BM who underwent resection survive longer than 24 months after resection.
P10.07.A A CLINICALLY COMPATIBLE<i>IN VITRO</i>DRUG-SCREENING PLATFORM IDENTIFIES THERAPEUTIC VULNERABILITIES IN PRIMARY CULTURES OF BRAIN METASTASES
Authors: S Jeising, J Trübel, J Felsberg, D Picard, M Wolter, K Kaulich, L Häberle, I Esposito, J Steinmann, J Cornelius, T Beez, M Rapp, M Sabel, A Nickel, M Remke, G Reifenberger, N Qin
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Approximately 20% of cancer patients (including lung, melanoma, breast, renal, and colorectal cancer patients) develop brain metastases. Current systemic therapies often show limited efficacy for brain metastasis treatment and support palliative care only. MATERIAL AND METHODS In this preclinical study, short-term cultured primary cancer cells from brain metastasis patients were molecularly characterized using next-generation sequencing and functionally evaluated using high-throughput in vitro drug screening to identify pharmacological treatment sensitivities. RESULTS Next-generation sequencing identified matched genetic alterations between brain metastasis tissues and corresponding patient-derived cultured cancer cells. Mutant allele frequencies indicated that short-term cultures of cancer cells reflect the existence of distinct subpopulations of cancer cells within brain metastases. This indicates that our short-term cultured primary brain metastasis cells are suitable models for recapitulating heterogeneity in the sensitivity of tumor cells to anti-cancer drugs. Employing our in-house high-throughput in vitro drug screening platform, we additionally screened primary cultures from the brain metastasis patients for response to 267 anticancer compounds, and integrated the molecular and high-throughput drug screening data sets. CONCLUSION Our preclinical study thus provides proof-of-concept for combining molecular profiling with in vitro drug screening for improved prediction of therapeutic vulnerabilities in brain metastasis patients. This approach could advance the use of patient-derived cancer cells in clinical practice and might eventually facilitate decision-making for personalized drug treatment.
P18.06.B EVALUATION OF P16 AND MTAP IMMUNOHISTOCHEMICAL EXPRESSION AS SURROGATE MARKERS OF CDKN2A/B DELETION IN MENINGIOMAS
Authors: A A Ricci, C Tampieri, F Nozzoli, A M Buccoliero, L Mangherini, L Verdun di Cantogno, S Osella-Abate, A Pellerino, F Bruno, R Rudà, D Garbossa, D Massi, P Cassoni, L Bertero
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Homozygous deletion (HD) of CDKN2A/B genes (chr. 9p21) is a molecular hallmark for meningiomas grading. However, testing is expensive and time-consuming. Immunohistochemical (IHC) evaluation of the CDKN2A (p16) and adjacent MTAP gene products has been proposed as a diagnostic surrogate of CDKN2A HD, with unsatisfactory or inconclusive results. MATERIAL AND METHODS CDKN2A status was assessed by FISH with the Zytolight SPEC CDKN2A/CEN 9 Dual Color probe (Zytovision©) in 68 meningiomas from 56 patients. A 15% cut-off of HD cells was used to define a sample as deleted. Negative (&amp;lt;10% positive cells) p16 (Ventana) and MTAP (Clone 2G4; Abnova) IHC were considered as a surrogate for CDKN2A HD. Since CDKN2A/B deletion in meningiomas is characterized by spatial and longitudinal heterogeneity, the same area selected for FISH analysis was assessed by IHC. Pearson Chi-square test for categorical variables and survival analysis with log-rank test and the Kaplan-Meier method were performed using the Stata/MP 17.0 software. RESULTS In our series, 29/56 (51.7%) patients were male, and median age at diagnosis was 69 years. Median overall survival (OS) from diagnosis was 37.9 months (27 months for HD cases and 39.3 months for non-HD). 51 (75%) samples were diagnosed as WHO grade 3 meningiomas, 11 (16.2%) as grade 2 and 6 (8.8%) as grade 1. 11 cases (16.2%) were CDKN2A-deleted by FISH. p16 IHC was negative in 25 (36.8%) cases, while MTAP IHC was negative in 24 (35.3%) cases. No correlation between these markers was observed (Cohen’s κ=-0.0202, p=0.7158). 5/11 (45.4%) deleted samples were negative for p16 staining, while 37/57 (64.9%) non-deleted samples displayed p16 positivity (sensitivity: 20%; specificity: 86.1%). MTAP IHC was negative in 8/11 (72.7%) deleted samples, whereas 41/57 (71.9%) non-deleted samples retained MTAP expression (sensitivity: 33.3%; specificity: 93.2%). Unlike p16 IHC, MTAP loss correlated with CDKN2A HD (p=0.005). To address intratumoral heterogeneity, FISH analysis was repeated on 2 samples with markedly variable p16 and MTAP stainings. For each sample, one positive and one negative area were analyzed, observing a correlation between IHC and HD FISH status. CONCLUSION MTAP IHC showed a higher correlation with CDKN2A HD compared to p16 IHC in meningiomas, even though the low sensitivity hinders its use in routine diagnostics. Nevertheless, the use of p16/MTAP IHC to select areas for FISH analysis could be considered to address intratumoral heterogeneity of CDKN2A status.
P13.11.B CLINICAL-RADIOMICS MODEL FOR LOW-GRADE GLIOMA SURVIVAL PREDICTION
Authors: A Neimantaite, L Carstam, T Gómez Vecchio, T Dunås, I Häggström, A Smits, A S Jakola
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Low-grade gliomas are by the latest WHO classification exclusively IDH-mutated tumors, and are further divided into astrocytomas (1p19q non co-deleted) and oligodendrogliomas (1p19q co-deleted). Radiomics, that is extraction of mathematical features of images, has prognostic potential and the method is able to capture properties of whole tumors, in contrast to typical biological samples. Our aim was to investigate how a radiomics prognostication model performs in relation to a clinical prognostication model for IDH-mutated tumors. MATERIAL AND METHODS 143 cases (71 astrocytomas and 72 oligodendrogliomas) were included in the analysis. Median follow-up time was 75 months. The data was divided in training and test set with 70:30 ratio. Four different radiomics models were investigated including image features extracted from tumor and peritumor zones respectively. RESULTS Preliminary results have shown best radiomics model performance for prognostication purposes in IDH-mutated tumors were based on the peritumoral zone 0-10 mm around the segmented tumor. This model resulted in a c-index of 0.88 on training set and 0.76 on test set in explaining the overall survival when the cohort of IDH-mutated tumors were analyzed together. The model will also be evaluated in the molecular subgroups and on an external test set, and finally compared to a clinical model. CONCLUSION Our findings will identify the top features in radiomics prognostication of IDH-mutated tumors, and also provide important data on the best area for radiomics extraction in these cases. The clinical implications of our findings will show whether radiomics adds additional value to the clinical model of low-grade glioma prognostication.
P02.08.B ROLE OF THE PROTEIN NETWORK OF THE PARACASPASE MALT1 IN SELF-RENEWAL PROPERTIES OF GLIOBLASTOMA CELLS
Authors: M Kerhervé, J Gavard
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most common and most aggressive brain tumor in adults. Despite standard treatment combining surgery, radiotherapy and chemotherapy, relapse is inevitable, making this cancer a major public health issue. Within this tumor reside cells with a stem-like character, called GSCs for Glioblastoma Stem-like Cells, which maintain, initiate, and propagate the tumor, making them a potential target to hinder glioblastoma. These cells constitute a reservoir of heterogeneous cells capable of differentiating into neural lineage cell types. In this context, lysosomal homeostasis plays a key role in the maintenance of the GSC reservoir. Furthermore, previous studies demonstrated that the paracaspase MALT1 is a major regulator of lysosomal homeostasis: MALT1 is required for GSC viability as well as for the maintenance of stemness by modulating the abundance of lysosomal proteins. This current study addresses the issue of the balance between self-renewal and viability of GSCs. In addition, this project aims to identify and characterize an actor of self-renewal mechanisms that does not impact the survival-death balance of primary cells from patients. MATERIAL AND METHODS An initial analysis combining DepMap and String Network databases allowed us to select potential relays of the MALT1 activity in GSCs. A functional screening was then set up and performed in GSCs derived from patients to identify among 20 candidates those regulating cell expansion without impacting viability. RESULTS The strategy of functional screening allowed the selection of 14 genes with a global viability effect, while only 2 genes were affecting self-renewal while sparing viability in vitro. We next pursued with one of the identified targets, from the IKK family. The involvement of this serine/threonine protein kinase was then confirmed in multiple patient cells and in CRISPR-mediated knock-out. Future experiments will decipher the involvement of this kinase in the self-renewal properties of GSCs. CONCLUSION This study highlights a putative candidate specifically operating on the self-renewal of glioblastoma cells, that does not affect the life-death balance. Future investigations will permit to characterize and understand the underlying mechanisms.